Intracellular glutathione is a main antioxidant of an organism and is an extremely important molecule for biophylaxis (Non-Patent Document 1). Glutathione is constituted of three amino acids (glycine, cysteine and glutamic acid) and is synthesized by a two-stage enzymatic reaction. But, since merely administration of the amino acids of three kinds as raw materials of glutathione does not increase glutathione in a cell, a complicated regulation mechanism is expected.
It is known that when glutathione in a nerve cell is experimentally decreased, neurodegeneration occurs (Non-Patent Document 2). In actual diseases, it is also known that glutathione decreases in a number of diseases such as neurodegenerative diseases (for example, Parkinson's disease and Alzheimer's disease), malignant tumors and infectious diseases. It is expected that if a remedy for increasing glutathione is available, such is quite useful, and realization thereof is desired (Non-Patent Documents 3 to 6). But, such a remedy does not exist.
EAAC1 (excitory amino acid carrier-1) is expressed on a cell membrane, and was discovered as a protein for uptaking glutamic acid into cells (glutamic acid transport protein). However, it is known that EAAC1 has a low ability as a glutamic acid transport protein and that other proteins (for example, GLT-1 and GLAST) are much more important as the glutamic acid transport protein (Non-Patent Documents 7 to 8). Thereafter, it was found out that EAAC1 has an ability to transport not only glutamic acid but also other amino acids including cysteine (Non-Patent Documents 9 to 11).
Furthermore, it was recently discovered that EAAC1 is a necessary protein for keeping the amount of intracellular glutathione (Non-Patent Document 12). It was presumed that the matter that EAAC1 has an ability to transport glutamic acid and cysteine, which are constituent amino acids of glutathione, contributes to this.
Accordingly, if a measure for activating EAAC1 is available, it may be theoretically possible to increase the amount of intracellular glutathione. However, molecules or compounds that bind with EAAC1 to activate it have not been discovered to date. Also, a point of concern about the development of drugs targeting EAAC1 is the fact that all of molecules and compounds binding with a transport protein on a cell membrane are inhibitors. For instance, there are examples including SSRI, an antidepressant for a serotonin transport protein; desipramine, an antidepressant for a noradrenaline transport protein; and reserpine, a depressor for an amine transport protein of nerve ending granules. Accordingly, it is thought that there is a high possibility that molecules or compounds targeting EAAC1 rather decrease the amount of glutathione, and actually, examples thereof exist (Non-Patent Document 13).
On the other hand, a protein referred to as GTRAP3-18 (glutamate-transporter-associated protein 3-18) as an in vivo molecule binding with EAAC1 exists. It is known that this GTRAP3-18 is often expressed in brain, spinal, kidney, heart and skeletal muscle and binds with EAAC1 to lower the transport ability of glutamic acid (Non-Patent Document 14). However, since the transport mechanism of EAAC1 is different in the respective amino acids (Non-Patent Documents 15 and 16), when GTRAP3-18 binds with EAAC1, how the transport ability of cysteine changes is unclear. Furthermore, how increase and decrease of GTRAP3-18 influence the amount of intracellular glutathione is quite unclear. An amino acid sequence of GTRAP3-18 and cDNA encoding GTRAP3-18 are described in Patent Document 1.    Patent Document 1: U.S. Pat. No. 6,808,893    Non-Patent Document 1: Dringen, Prog Neurobiol, 62: 649-671, 2000    Non-Patent Document 2: Jain et al., Proc Natl Acad Sci, 88: 1913-1917, 1991    Non-Patent Document 3: Exner et al., Wien Klin Wochenschr, 112: 610-616, 2000    Non-Patent Document 4: Lomaestro et al., Ann Pharmacother, 29: 1263-1273, 1995    Non-Patent Document 5: Reid and Johoor, Curr Opin Clin Nutr Metab Care, 4: 65-71, 2001    Non-Patent Document 6: Townsend and Tew, Oncogene, 22: 7369-7375, 2003    Non-Patent Document 7: Kanai et al., Neuroreport 6: 2357-2362, 1995    Non-Patent Document 8: Robinson and Dowd, Adv Pharmacol, 37: 69-115, 1997    Non-Patent Document 9: King, et al., Cardiovasc Res, 52: 84-94, 2001    Non-Patent Document 10: Chen and Swanson, J Neurochem, 84: 1332-1339, 2003    Non-Patent Document 11: Himi et al, J Neural Transm, 110: 1337-1348, 2003    Non-Patent Document 12: Aoyama et al., Nature Neuroscience, 9: 119-126, 2006    Non-Patent Document 13: Esslinger et al., Neuropharmacology, 49: 850-861, 2005    Non-Patent Document 14: Lin et al., Nature, 410: 84-88, 2001    Non-Patent Document 15: Bendahan, A. et al., J Biol Chem, 275: 37436-37442, 2000    Non-Patent Document 16: Borre and Kahner, J Biol Chem, 279: 2513-2519, 2004